In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.

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The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM.

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The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term “microbiome” is used to describe the diverse community of micro-organisms existing within the gastrointestinal tract. The gut microbiome plays an important role in oestrogen metabolism through its ability to deconjugate oestrogens within the gut resulting in their reabsorption. Therefore, it is not unsurprising that “dysbiosis”, the disruption of normal gut microbiota composition, is now thought to play a role in the development of the disease, as women with breast cancer have been shown to have altered gut microbiota and this has been correlated with tumour characteristics. There is emerging evidence to suggest that the gut microbiota may also impact on breast cancer treatment, by mediating both drug efficacy and toxicity. The present review will discuss the influence of the gut microbiota on systemic treatments for breast cancer, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, endocrine therapy and immunotherapy as well as other targeted treatments.

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Since the identification and cloning of the cannabinoid receptor 2 (CB₂R), several studies focused on the characterization of its physiological and pathological role. Initially, CB₂R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB₂R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB₂R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB₂R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB₂R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders.

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The pathogenic basis behind some of the most prevalent neurodegenerative diseases in advanced societies, known as proteinopathies, deals with alterations in protein homeostasis. Despite the broad diversity of clinical symptoms, they share a remarkably common feature that is the serious neuronal loss in several disease-specific brain regions due to the presence of toxic aggregations of misfolded proteins. So far, research efforts have been insufficient to decipher the exact molecular mechanisms that trigger the conformational change from a functional healthy protein to its pathological version. This is a sine qua non condition to progress in developing new approaches and treatments for these diseases for which there is no cure. Currently, it is well accepted that perturbations in gut microbiota composition negatively impact a wide range of brain processes via the gut-brain axis which increases host susceptibility to neurodegenerative disorders. In this context, modulate the microbial ecosystem colonizing the gastrointestinal tract may be a promising therapeutic approach in the management of proteinopathies. This review aims to provide an updated view of the role that gut microbiota poses in the pathogenesis of Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, the most common neurodegenerative proteinopathies, and of the possibility of translating this knowledge into effective and safe clinical microbiota-based interventions, especially those designed to afford neuroprotection.

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Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic.

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The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism.

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As the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a new virus, the current knowledge on the immunopathogenesis of this newly emerged SARS-CoV-2 is beginning to unravel with intensive ongoing global research efforts. Although a plethora of new studies have been published in a short space of time describing how the virus causes disease and incurs insults on the host immune system and the underlying immunopathogenic mechanisms remain to be elucidated. Thus, the discussion in this review is based on the most current knowledge on the immunopathogenesis of SARS-CoV-2 that has emerged in the past 12 months. The main objective is to shed light on the most current concepts in immunopathological aspects of the lung, bloodstream, and brain caused by the SARS-CoV-2, which has led to the current pandemic resulting in > 100 million infections and > 2 million deaths, and ongoing.

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Arginase-1 (Arg1) and the inducible nitric oxide synthase 2 (NOS2) compete for the common substrate L-arginine, semi-essential amino acid, and central intestinal metabolite. Both enzymes exhibit various, sometimes opposing effects on immune responses, tissue regeneration, or microbial growth and replication. In sub-mucosal tissues of patients suffering from inflammatory bowel disease (IBD), similar as in experimental colitis, the expression and activity of both enzymes, Arg1 and NOS2 are more prominent than in respective controls. Accordingly, the metabolism of L-arginine is altered in IBD patients. Thus, L-arginine represents a promising medical target for clinical intervention in these devastating diseases. Previous studies primarily focused on the host side of L-arginine metabolism. Initial reports using Arg1 inhibitors generated conflicting results in murine colitis models. Subsequently, only the generation of conditional Arg1 knockout mice allowed reliable functional analyses of Arg1 and the L-arginine metabolism in the immune system. Utilizing cell-specific conditional Arg1 knockouts, we have recently reported that Arg1, surprisingly, hampered the resolution of experimental colitis due to the restriction of the intraluminal availability of L-arginine. Reduced levels of L-arginine restrained the compositional diversity of the intestinal microbiota and subsequently the mutual metabolism between the microbiota and the host. Thus, the intraluminal microbiota represents a potential therapeutic target for L-arginine metabolism aside from host-dependent L-arginine consumption.

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Some have said that it is inappropriate and perhaps impossible to consider wave and Windkessel phenomena simultaneously. For 50 years, arterial hemodynamics has been dominated by the frequency-domain “impedance analysis” in which it was assumed that all variations in aortic pressure and flow were caused only by forward- and backward-going waves. This paper is a review of the results of incorporating the effects of Frank’s Windkessel. We have taken the view that measured aortic pressure is the sum of a Windkessel component and forward-going and backward-going wave components. When the Windkessel component is initially subtracted out, the pattern of propagation and reflection of wave components becomes clear. Furthermore, this analysis obviates the implications of impedance analysis that have not been explained satisfactorily.

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Immunotherapy is a unique approach to treat cancer that targets tumours besides triggering the immune cells. It attempts to harness the supremacy and specificity of immune cells for the regression of malignancy. The key strategy of immunotherapy is that it boosts the natural defence and manipulates the immune system at both cellular and molecular levels. Long-lasting anti-tumour response, reduced metastasis, and recurrence can be achieved with immunotherapy than conventional treatments. For example, targeting cytotoxic T-lymphocyte antigen-4 (CTLA4) by monoclonal antibody is reported as an effective strategy against cancer progression in vivo and chimeric antigen receptor (CAR) modified T-cells are known to express a stronger anti-tumour activity. CTLA4 and CAR are, therefore, beneficial in cancer immunotherapy; however, in clinical settings, both are expensive and cause adverse side effects. Nanomaterials have augmented advantages in cancer immunotherapy, besides their utility in effective delivery and diagnostics. In particular, materials based on lipids, polymers, and metals have been sought-after for delivery technologies. Moreover, the surface of nanomaterials can be engineered using ligands, antigens, and antibodies to target immune cells. In this sense, checkpoint inhibitors, cytokines, agonistic antibodies, surface receptors, and engineered T-cells are promising to regulate the immune system against tumours. Therefore, emerging nanomaterials that can be used for the treatment of cancer is the prime focus of this review. The correlation of mode of administration and biodistribution of various nanomaterials is reviewed here. Besides, the acute and chronic side effects and outcome of clinical trials in the context of cancer immunotherapy are discussed.

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The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

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The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

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Skin is the largest organ of the body having multifunctional activities. It has a dynamic cellular network with unique immunologic properties to maintain defensive actions, photoprotection, immune response, inflammation, tolerogenic capacity, wound healing, etc. The immune cells of the skin exhibit distinct properties. They can synthesize active vitamin D [1,24(OH)₂D₃] and express vitamin D receptors. Any difficulties in the cutaneous immune system cause skin diseases (psoriasis, vitiligo, atopic dermatitis, skin carcinoma, and others). Vitamin D is an essential factor, exhibits immunomodulatory effects by regulating dendritic cells’ maturation, lymphocytes’ functions, and cytokine production. More specifically, vitamin D acts as an immune balancing agent, inhibits the exaggeration of immunostimulation. This vitamin suppresses T-helper 1 and T-helper 17 cell formation decreases inflammatory cytokines release and promotes the maturation of regulatory T cells and interleukin 10 secretion. The deficiency of this vitamin promotes the occurrence of immunoreactive disorders. Administration of vitamin D or its analogs is the therapeutic choice for the treatment of several skin diseases.

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Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.

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